Abstract
BackgroundEGFR overexpression has been described in many human tumours including gastric cancer. In NSCLC patients somatic EGFR mutations, within the kinase domain of the protein, as well as gene amplification were associated with a good clinical response to EGFR inhibitors. In gastric tumours data concerning structural alterations of EGFR remains controversial. Given its possible therapeutic relevance, we aimed to determine the frequency and type of structural alterations of the EGFR gene in a series of primary gastric carcinomas.MethodsDirect sequencing of the kinase domain of the EGFR gene was performed in a series of 77 primary gastric carcinomas. FISH analysis was performed in 30 cases. Association studies between EGFR alterations and the clinical pathological features of the tumours were performed.ResultsWithin the 77 primary gastric carcinomas we found two EGFR somatic mutations and several EGFR polymorphisms in exon 20. Six different intronic sequence variants of EGFR were also found. Four gastric carcinomas showed balanced polysomy or EGFR gene amplification. We verified that gastric carcinoma with alterations of EGFR (somatic mutations or copy number variation) showed a significant increase of tumour size (p = 0.0094) in comparison to wild-type EGFR carcinomas.ConclusionWe demonstrate that EGFR structural alterations are rare in gastric carcinoma, but whenever present, it leads to tumour growth. We considered that searching for EGFR alterations in gastric cancer is likely to be clinically important in order to identify patients susceptible to respond to tyrosine kinase inhibitors.
Highlights
epidermal growth factor receptor (EGFR) overexpression has been described in many human tumours including gastric cancer
EGFR Mutation Screening From the 77 gastric carcinomas analysed, EGFR mutations in exons 18–21 were detected in 2.6% (2/77) of the cases (Fig. 1A)
EGFR Copy Number Variation Screening The analysis of EGFR copy number, as assessed by fluorescence in situ hybridization (FISH), was only possible in 30 of the 77 cases analysed for EGFR mutations
Summary
EGFR overexpression has been described in many human tumours including gastric cancer. The members of the RTK superfamily of ERBB receptors are glycoproteins that consist of an extracellular domain where the binding of ligands takes place, a short lipophilic transmembrane domain, and an intracellular domain carrying the tyrosine kinase activity [3,4]. They are expressed in several tissues of epithelial, mesenchymal and neuronal origin, where they play pivotal roles in development, proliferation and differentiation. We demonstrated that EGFR activation is associated to loss of function of Ecadherin, in vitro [12]
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